Abstract

Antimitotic drugs are often administered as first‐line chemotherapy in several malignancies. However, their clinical success is often limited by acquired chemoresistance and disease relapse. The anti-proliferative basis of these drugs is induction of mitotic arrest culminating in cell death. Mitotic slippage occurs when cells exit mitosis and “slip” into interphase without chromosome segregation and cytokinesis. Little is known about how cells post-slippage influence outcome of treatment. Here, we demonstrate that post-slippage cells exhibit paracrine pro-tumourigenic potential following senescence and senescence-associated secretory phenotype development. This occurs in an autophagy-p53 axis-dependent manner, with autophagic inhibition in post-slippage cells bypassing senescence and leading to cell death. Indeed, the autophagy inhibitor Chloroquine and microtubule poisons synergistically inhibited tumour growth in mice. Hence, regimens targeting the senescence phenotype could provide a potential effective combinatorial strategy with antimitotic drugs. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.